As is known in the art a human heart comprises pacemaker cells and cardiac muscle cells (myocardium). Cardiac muscle cells are stimulated to contract by an electrical signal. An incident electrical signal causes a cardiac cell to undergo depolarisation. The cell slowly repolarises after it has been stimulated in this way. A contraction in a cardiac muscle cell causes changes to the environment of a neighbouring cell, which can trigger contraction in the neighbouring cell. In this way a signal is transmitted through the muscle of the heart.
In the resting state cells are negative (having a resting potential of about −70 mV). When a muscle cell is stimulated the potential inside increases (i.e. becomes less negative), in a process known as “depolarisation”. Once the cell has depolarised it slowly repolarises.
Furthermore, all heart muscle cells are self-stimulating. This is due to the fact that they slowly depolarise by themselves, in the absence of any stimulating current. However, in a normal heartbeat the stimulation of the heart muscle cells is regulated by a pacemaker cell in the heart. The pacemaker cell is also self-stimulating (i.e. it also depolarises by itself), but the period of this depolarisation is faster than that of the heart muscle cells, so that in a normal heartbeat the muscle cells are stimulated by the action of the pacemaker cell before the muscle cells spontaneously depolarise. When the pacemaker cell depolarises it transmits an electrical signal to the heart muscle cells, which are then stimulated in an ordered manner (the wave of stimulation is started by pacemaker cells, and passes through the heart as the stimulated muscle cells stimulate neighbouring muscle cells). The ordered stimulation of the heart muscle means that the heart contracts, pumping blood around the body. Once a heart muscle cell has been stimulated it cannot be stimulated again for certain time known as the refractory period (this is related to the time taken for the cell to repolarise sufficiently to be stimulated again).
An arrhythmia (or dysrhythmia) occurs where the muscles of the heart quiver, and the normal rhythm of the heart muscles is disrupted. A fibrillation is an example of a serious arrhythmia, where there is a lack of coordination of the contraction of the muscle tissue of the large chambers of the heart. A fibrillation can be affect an atrium of the heart (atrial fibrillation (AF)), or a ventricle of the heart (ventricular fibrillation (VF)). Ventricular fibrillation tends to be a more serious cardiac condition than atrial fibrillation, since the ventricles of the heart pump the blood to the body, and to the lungs.
VF is a cause of sudden cardiac death (SCD) which can affect apparently healthy individuals. Certain cardiac conditions pre-dispose people to VF. Furthermore, post-coronary patients, i.e. patients who have had a heart attack, for example a coronary thrombosis which has lead to myocardial infarction (AMI or MI) and scarring of the muscle tissue of the heart, may also be at risk of VF. Heart conditions such as hypertropic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) congestive heart failure (CHF) and long QT syndrome (LQTS) pre-dispose people to VF. Therefore, these people are at risk of SCD, and it is desirable to determine high-risk patients so that they can be treated accordingly (such as by inserting an implantable defibrillator).
People with HCM have fibrosis and disarray in the myocardium, which are likely to create delays dues to tortuous conduction, and local block effects; further, the tissue shows an increase in transverse propagation. LQTS patients show a longer QT period on the ECG. In LQTS there is normal myocardial architecture, but these patients may still be prone to VF, depending on their LQTS phenotype.
An important phenomenon relating to fibrillation is that of re-entry. Re-entry basically involves a muscle cell being stimulated twice by one electrical impulse sent by the pacemaker cells. The muscle cell is stimulated once, becomes refractory, repolarises and is then stimulated again after its refractory period has elapsed. Re-entry may be caused by disruption in the heart substrate, such as by scar tissue, for example.
An example of disruption of conduction through a heart having conduction blocks such as those seen in HCM patients will now be described with reference to FIGS. 1 to 8.
FIG. 1 is a schematic diagram showing a heart following a previous heart beat, such that an area of the heart is still refractory. The heart myocardium 10 has an area of homogenous tissue 12, and an area of fibrous tissue 14. FIG. 1 shows potential conduction paths through the homogenous tissue, represented by straight lines 16, and indicating rapid conduction paths. In contrast, the conduction paths through the fibrous tissue region 14 are shown as twisted and curved, denoted by lines 18, indicative of slower conduction paths in this region. There is a region (hereafter called “the region 20”) which effectively has a prolonged refractory period 20. The region 20 receives the signal passing through the homogeneous tissue 12, and the delayed signal passing though fibrous tissue 14. This means that the area is refractory following a previous heart beat.
FIG. 2 is a schematic diagram showing an activation front 22 of conduction for the next heart beat through myocardium. FIG. 2 shows the region 20 which is still refractory following the last beat. As shown in FIG. 3, the activation front 22 advances until it reaches the region 20, which, being refractory, cannot be stimulated by the activation front 22, and the activation front 22 deflects around the region 20 (see FIG. 4). As can be seen in FIG. 4, part of the activation front enters the fibrous tissue region 14, whereupon part of the wavefront slowly advances though the conduction paths 18 in the fibrous tissue 14 as shown in FIG. 5. The remainder of the activation front 22 has now passed out of the region of myocardium 10. FIG. 6 shows the region 20, which was initially refractory, beginning to repolarise, whilst the activation front 22 advances towards the region 20. In FIG. 7 the region 20 which was initially refractory has fully repolarised, and the activation front 22 which passed through the fibrous tissue 14 now depolarises the region 20. FIG. 8 shows the activation front 22 leaving the region 20, and depolarising the surrounding myocardium 10, which is no longer refractory. This results in an activation front 22 which is effectively travelling in the opposite direction to that in which it was travelling initially, leading to spiral waves, as indicated by the arrows shown in FIG. 8. As a result, the activation front 22 continues to stimulate muscle tissue 10, causing uncoordinated contractions in the myocardium 10, leading to an arrhythmia, and ventricular fibrillation.
A known way of detecting whether a patient is at risk of VF is to perform a paced electrogram process, by inserting one input electrode and one or more output electrodes into the heart, and applying a pacing signal to the input electrodes. The output electrodes are typically inserted into the right ventricular septum, the inferior wall of the right ventricle and the right ventricular outflow tract. An electrogram of the potential recorded by the output electrodes is then produced. Electrograms, and other related graphical representations of output signals will also be referred to herein as “electrogram trace” and “trace”.
FIG. 9 shows a schematic diagram of a wavefront from a pacing signal passing through homogeneous tissue, in a healthy heart, for example. Two recording electrodes 40, 42 are shown, and the wavefront 44 reaches these in a straightforward manner, giving the electrogram 46 shown, having a single peak, A.
FIG. 10 shows a schematic diagram of a wavefront from a pacing signal passing though diseased tissue 14. As described above with reference to FIGS. 1 to 8, the fibrous tissue 14 causes a slowing of the conduction paths through the diseased region 14. This results in a number of signals being recorded by the recording electrodes 40, 42: in this example, peaks A, B, C, D and E can be seen on an electrogram 60, each peak corresponding to a conduction path having the same letter.
FIG. 11 shows a schematic diagram of pacing sequence 70 which can be used to stimulate at an electrode placed in a region of a patient's heart. As can be seen, the pacing sequence comprises a drive chain S1 with an extrastimulus applied every third beat. This extrastimulus is premature, in that the pacing interval, S1S2 (i.e. the interval between a pulse S1 and a pulse S2) is shorter than the pacing interval S1S1 (i.e. the interval between successive S1 pulses). The pacing interval is also referred to herein as the “coupling interval”. In one arrangement the coupling interval S1S2 decreases in 1 ms steps, but the skilled person will appreciate that other coupling intervals are possible, and the shortest period used usually corresponds to the ventricular effective refractory period (VERP). The purpose of applying this stimulus is to stress the heart, to so that effects associated with VF can be displayed. The electrogram produced from this technique is known as an intracardiaelectrogram.
FIG. 12 shows a stimulus produced from a heart, paced with a pulse such as that shown in FIG. 11, the effects of the pulsing being recorded at 3 points in the right ventricle. The S1S1 coupling interval is 490 ms, and the S1S2 coupling interval is 249 ms in this example.
FIG. 13 shows further stimuli produced in a similar way to those in FIG. 12 at each of three recording sites. Furthermore, FIG. 13 shows a comparison between electrograms 80a, 80b, 80c recorded at an S1S2 interval of 350 ms and 250 ms for each of the sites. As can be seen from this Figure, the electrogram traces show an increase in the number of peaks, and an increase in the delay in the signal from the initial pulse 82 (which can be seen on the left hand side of the traces). The interval between the electrograms recorded at 350 and 250 ms differs at each site, showing that the delays are due to activation front passing through the myocardium rather than due to another effect, such as increased stimulus-to-tissue delay (since, if the delay were due to the latter effect, each of the traces would show the same increase in delay).
FIG. 14 shows examples of traces at various S1S2 coupling intervals, showing the differences in traces between a control patient and an HCM patient. Again, as can be seen, the HCM trace shows an increase in the number of peaks, and an increase in the horizontal spread of the trace.
FIG. 15 shows an electrogram 90, with a close up view showing noise in the trace. Each peak of the electrogram is analysed, and can be plotted as a function of the S1S2 coupling interval at which the trace was taken. This is shown in more detail in FIGS. 18 and 19, discussed below.
International patent application having publication number WO94/02201 discusses the use of such graphs in calculating a risk of a patient having myocardial disarray from suffering a VF. Some patients, however, do not exhibit myocardial disarray, but are nevertheless prone to VF and to SCD (such as those patients having long QT syndrome (LQTS)); thus, whilst extremely useful, the techniques described in WO94/02201 are not sufficiently developed for use in identifying all patients at risk from SCD. Various alternative methods have been developed, e.g. on the basis of genotype identification; while certain genotypes of LQTS have been identified, each genotype has a number of different associated phenotypes, meaning that two or more people having the same gene or set of genes associated with LQTS may have hearts displaying different physical characteristics. Further, it seems that different phenotypes have different amounts of risk to VF. As a result, techniques which involve testing the genotype of a patient cannot be used to determine whether an LQTS patient is susceptible to VF.
It is therefore desirable to find a way in which different cardiac conditions, predisposing a patient to VF can be determined from the same experiment and/or the same method of analysis.
It is an object of embodiments of the present invention to provide a system for analyzing electrograms.